Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary growth factor receptors involved in angiogenesis and lymphomagenesis can be grouped into the vascular endothelial growth factor (VEGF) receptors and related families. Inhibition of VEGF and other growth factors, including c-Abl, c-Kit, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and insulin-like growth factor (IGF), or their receptors containing tyrosine kinase domains by antiangiogenesis drugs disrupts cell survival signal transduction pathways and may contribute to the proapoptotic pathways in malignant cells. However, clinical trials suggest that signal transduction inhibitors have considerable antitumor activity when used as single agents only for a short time, most likely due to the development of drug resistance by the host or by the tumor cells. In order to prevent this problem and to augment their antitumor efficacy, these agents could be administered in combination with cytotoxic antineoplastic drugs. We hypothesized that the combination of the antiangiogenesis tyrosine kinase inhibitors with cytotoxic drugs would produce synergistic drug regimens. Two human T-lymphoblastic leukemia cell lines that express VEGF-R1, CEM/0 (wild-type, WT) and the drug-resistant clone CEM/ara-C/I/ASNase-0.5-2, were utilized in the drug combination studies. NSC 680410, a tyrosine kinase inhibitor given at 0.1 to 1 microM for 72 h, inhibited VEGF secretion and leukemic cell growth at 90% of vehicle-treated control cultures with an IC50 value of less than 1 microM. The cytotoxic drugs idarubicin (IDA), fludarabine (Fludara), and cytosine arabinoside (ara-C) were used for the various drug combinations. One-, two-, three-, and four-drug treatments were tested. Cell viability was documented by the MTT assay and photomicrographic estimation of apoptotic cells. Both the combination index (CI) and isobologram evaluations demonstrated strong synergism between these drugs and the tyrosine kinase inhibitor. NSC 680410 was highly synergistic with IDA, IDA + ara-C, and IDA + Fludara + ara-C, over the respective cytotoxic drug regimens at concentrations easily achieved in patient plasma. NSC 680410 potentiated the activity of IDA in both leukemia cell lines by 17.8- and 221.4-fold in the WT and drug-resistant line, respectively. The activity of NSC 680410 + IDA + ara-C was also potentiated by 58.8-fold in the WT line, and the activity of NSC 680410 + IDA + Fludara + ara-C by 2.4- and 6.47x10(6)-fold in the WT and drug-resistant lines, respectively. The results suggest that IDA was not needed for optimal synergistic activity in the CEM/0 cells, but IDA was a necessary component to obtain drug synergism in the drug-resistant clone. Similarly, STI571 (imatinib mesylate, Gleevec), the p210(bcr/abl) tyrosine kinase inhibitor, demonstrated synergism with Fludara + ara-C or IDA + ara-C. Most importantly STI571 showed synergism with NSC 680410, suggesting that these drugs inhibit different tyrosine kinase domains in human leukemia cells. Lastly, pretreatment of leukemic cells with NSC 680410 showed additivity with gamma radiation in comparison to either treatment modality alone. The data, taken together, suggest that by inhibiting the pro-survival signal transduction pathway (VEGF-R1) and DNA replication by cytotoxic drugs, leukemic cells undergo apoptosis in a synergistic manner. In conclusion, the combinations of antiangiogenesis and DNA-damaging cytotoxic drugs are highly synergistic regimens in both WT and drug-resistant leukemic cell lines and they should be examined further.
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PMID:Determination of drug synergism between the tyrosine kinase inhibitors NSC 680410 (adaphostin) and/or STI571 (imatinib mesylate, Gleevec) with cytotoxic drugs against human leukemia cell lines. 1282 97

Fourteen adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) were studied to evaluate the role of imatinib prior to allogeneic stem cell transplantation (SCT). Of these, 12 patients were in complete hematologic response (CHR), and 2 were refractory. Imatinib was administered as an interim schedule after each chemotherapy course. After the first imatinib cycle, 11 patients remained in sustained CHR with a decrease in the BCR-ABL/ABL ratios (0.89 logs), and one refractory patient achieved CHR. Meanwhile, 2 patients were resistant to imatinib. Ten patients receiving a second imatinib cycle following consolidation showed sustained CHR, including 2 molecular CR, with a further decrease in the BCR-ABL/ABL ratios (0.19 logs). Twelve patients underwent SCT in a favorable status, and of these, 11 are still alive in a leukemia-free status at 9 to 28+ months after SCT. First-line imatinib interim therapy appears to be a useful strategy to bridge the time to SCT for patients with Ph+ ALL.
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PMID:Minimal residual disease-based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. 1284 84

We studied 128 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT). Disease at the time of treatment with Imatinib was in chronic phase (CP) in 51 patients, accelerated phase (AP) in 31 and blastic crisis (BC) in 46. Of the 51 patients in CP, 14 were in cytogenetic and two in molecular relapses. The median interval between relapse and Imatinib therapy was 5 months (0-65). A total of 50 patients had failed treatment with donor lymphocyte infusions prior to Imatinib. The overall hemato-logical response rate was 84% (98% for patients relapsing in CP). The complete cytogenetic response (CCR) was 58% for patients in CP, 48% for AP and 22% for patients in BC. Complete molecular responses were obtained in 25 patients (26%), of whom 21 were in CP or AP. With a median follow-up of 9 months, the estimated 2-year survival for CP, AP and BC patients was 100, 86 and 12%, respectively. Out of 79 evaluable patients, 45 (57%) achieved full donor and 11 (14%) mixed chimerism after Imatinib. We conclude that Imatinib has significant activity against CML in relapse after allogeneic SCT. Durable cytogenetic and molecular remissions are obtainable in patients in CP.
Leukemia 2003 Sep
PMID:Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. 1297 Jul 70

The antileukaemic tyrosine kinase inhibitor, imatinib, has been reported to inhibit specifically the growth of bcr-abl expressing CML progenitors at levels of 0.1-5.0 microM, by blocking the ATP-binding site of the kinase domain of bcr-abl. Inhibition of the c-abl, platelet-derived growth factor receptor and stem cell factor receptor (c-kit) tyrosine kinases by imatinib has also been reported. Here, we demonstrate that imatinib significantly inhibits in vitro monocyte/macrophage development from normal bone marrow progenitors, while neutrophil and eosinophil development was less affected. Monocyte/macrophage inhibition was observed in semisolid agar and liquid cultures at concentrations of imatinib as low as 0.3 microM. The maturation of monocytes into macrophages was also found to be impaired following treatment of cultures with 1.0 microM imatinib. Imatinib blocked monocyte/macrophage development in cultures stimulated with and without M-CSF, suggesting that inhibition of the M-CSF receptor, c-fms, by imatinib was unlikely to be responsible. Imatinib may therefore have an inhibitory activity for other kinase(s) that play a role in monocyte/macrophage differentiation. This inhibition of normal monocyte/macrophage development was observed at concentrations of imatinib achievable pharmacologically, suggesting that imatinib or closely related derivatives may have potential for the treatment of diseases where monocytes/macrophages contribute to pathogenesis.
Leukemia 2003 Sep
PMID:Imatinib inhibits the in vitro development of the monocyte/macrophage lineage from normal human bone marrow progenitors. 1297 Jul 69

STI-571 (imatinib, Gleevec, Glivec, CGP 57148) is an inhibitor of the Abl group of protein-tyrosine kinases. One of these enzymes, the Bcr-Abl oncoprotein, results from the fusion of the BCR and ABL genes that result from the reciprocal chromosomal translocation that forms the Philadelphia chromosome. The Philadelphia chromosome occurs in 95% of people with chronic myeloid leukemia. ABL is the cellular homologue of the oncogene found in murine Abelson leukemia virus, and BCR refers to breakpoint cluster region. The Bcr-Abl oncoprotein exhibits elevated protein-tyrosine kinase activity, which is strongly implicated in the mechanism of development of chronic myeloid leukemia. STI-571 is effective in the treatment of the stable phase of chronic myeloid leukemia. The c-Abl protein kinase domain exists in an active and inactive conformation. STI-571 binds only to the inactive state of the enzyme as shown by X-ray crystallography. The drug binds to a portion of the ATP-binding site and extends from there into adjacent hydrophobic regions. STI-571 is a competitive inhibitor of Abl kinase with respect to ATP. Resistance to STI-571 is often the result of mutations in residues of the Bcr-Abl kinase that ordinarily bind to the drug. Inhibition of target protein kinases represents an emerging therapeutic strategy for the treatment of cancer.
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PMID:STI-571: an anticancer protein-tyrosine kinase inhibitor. 1367 30

Imatinib has marked antileukemic activity in advanced Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), but secondary resistance develops rapidly, reflecting the limitations of single-agent therapy. Experimental data suggest that interferon-alpha (IFN-alpha) enhances the antileukemic activity of imatinib. We therefore examined combined imatinib and low-dose IFN-alpha in six patients with Ph+ALL who were ineligible for stem cell transplantation. All patients had received imatinib for 0.5-4.8 months prior to IFN-alpha, for relapsed (n=3) or refractory (n=1) Ph+ALL or as an alternative to chemotherapy following severe treatment-related toxicity (n=2). Five patients were in hematologic remission (CR) with minimal residual disease (MRD+), one patient was refractory to imatinib. Four of the five MRD+ patients are alive in CR after a median treatment duration of 20 (11-21) months. Two of these patients are in continuous CR 21 months after imatinib was initiated, while the other two patients experienced an isolated meningeal relapse that was successfully treated with additional intrathecal chemotherapy. Sustained molecular remissions were achieved in three patients and are ongoing 13 and 10.5 months after central nervous system (CNS) relapse and 6 months after starting concurrent IFN-alpha and imatinib, respectively. Marrow relapse occurred in one of the five MRD+ patients. Combination treatment was associated with a complete marrow response of 5 months duration in the imatinib-refractory patient. Imatinib combined with low-dose IFN-alpha may achieve prolonged hematologic and molecular remissions in a subset of patients with advanced Ph+ALL, who are not candidates for allogeneic SCT. CNS prophylaxis is necessary and may enhance the antileukemic activity of imatinib and IFN-alpha.
Leukemia 2003 Oct
PMID:Efficacy and safety of imatinib mesylate (Glivec) in combination with interferon-alpha (IFN-alpha) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). 1451 38

Studies of the mechanism of action of a shikonin derivative, beta-hydroxyisovalerylshikonin (beta-HIVS), have revealed that beta-HIVS inhibits the protein tyrosine kinase (PTK) activities of the receptor for epidermal growth factor and v-Src. In this review, we compare the characteristics of the inhibition of PTK activity by beta-HIVS with those of other inhibitors of PTKs. The chemical structure of beta-HIVS is completely different from that of ATP and it does not resemble any of the PTK inhibitors reported to date, except that it includes the benzylidene moiety. In contrast to most PTK inhibitors, the mechanism of inhibition by beta-HIVS is non-competitive with respect to ATP, but competitive with respect to its peptide substrate. This feature of the mechanism of inhibition of PTK by beta-HIVS suggests that it might be useful in a clinical setting with other PTK inhibitors. When Bcr-Abl-positive, human leukemia K562 cells were treated simultaneously with beta-HIVS and STI571 (Gleevec), these compounds had a synergistic effect on both the induction of apoptosis in K562 cells and the inhibition of the phosphorylation activity of PTK, probably because the mechanism of interference with phosphorylation by beta-HIVS and the binding site of beta-HIVS are different from those of STI571.
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PMID:A shikonin derivative, beta-hydroxyisovalerylshikonin, is an ATP-non-competitive inhibitor of protein tyrosine kinases. 1455 1

Imatinib mesylate (STI571, Glivec), a 2-phenylaminopyrimidine small-molecule ATP competitor-type kinase inhibitor, proved to be active in Philadelphia-positive leukemias. Resistance toward imatinib develops frequently in advanced-stage Philadelphia-positive leukemia, and is even observed in chronic-phase chronic myelogenous leukemia. Point mutations within the BCR-ABL kinase domain emerged as a major mechanism of resistance toward imatinib. Mutations occur at positions that determine specific contacts of imatinib to the ATP-binding site. We aimed to examine whether pyrido-pyrimidine-type kinase inhibitors were capable of inhibiting both wild-type and mutant forms of BCR-ABL. We screened 13 different pyrido-pyrimidine with cells expressing wild-type and mutant BCR-ABL. All of the substances specifically suppressed the Bcr-Abl dependent phenotype and inhibited Bcr-Abl kinase activity with higher potency than imatinib. Two of the most active compounds were PD166326 and SKI DV-M016. Interestingly, these compounds suppressed the activation loop mutant Bcr-Abl H396P as effectively as wild-type Bcr-Abl. In addition, nucleotide-binding loop mutations (Y253H, E255K, and E255V) were selectively and potently inhibited. In contrast, T315I, a mutant located at a position that makes a direct contact with imatinib, was not affected. This observation is consistent with the hypothesis that unlike imatinib, pyrido-pyrimidine inhibitors bind Bcr-Abl regardless of the conformation of the activation loop. We conclude that pyrido-pyrimidine-type kinase inhibitors are active against different frequently observed kinase domain mutations of BCR-ABL that cause resistance toward imatinib. Resistance as a consequence of selection of mutant BCR-ABL by imatinib may be overcome using second-generation kinase inhibitors because of their higher potency and their ability to bind Bcr-Abl irrespective of the conformation of the activation loop.
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PMID:Inhibition of wild-type and mutant Bcr-Abl by pyrido-pyrimidine-type small molecule kinase inhibitors. 1455 29

Imatinib mesylate (STI571, Glivec), a signal transduction inhibitor used as a single agent demonstrates significant activity in patients with chronic myelogenous leukaemia (CML). Nevertheless, the interaction between STI571 and other antileukaemic drugs such as hydroxyurea, interferon alpha or cytarabine have also been investigated in order to further improve its effectiveness. In this study we have tried to answer the question if the combination of STI571 with purine nucleoside analogues (PNAs)- cladribine (2-CdA) and fludarabine (F-ara-A) intensifies the antiproliferative effect on granulocyte-macrophage progenitor cells (CFU-GM) from patients with CML as well as from normal persons. Our studies were based on the method of semisolid CFU-GM cultures in vitro. We added STI571 or PNAs singly to the culture, each of the drugs at three concentrations, as well as in combinations of the concentrations used. We showed that STI571 (0.5, 1.0 and 2.0 microM) used alone inhibited the colony growth of CML CFU-GM, as compared to CFU-GM derived from normal donors (p = 0.03; p = 0.0004; p = 0.0001). We also observed that STI571 used together with 2-CdA (5,10 and 20 microM) or F-ara-A (0.2, 0.4 and 0.8 microM) at all the combinations significantly inhibited the colony growth of CML CFU-GM, as compared either to the control or to STI571 used alone (p < 0.05). In addition, the differences between CML and normal CFU-GM colony growth inhibition after the use of the combination of the highest concentrations of STI571 either with 2-CdA or F-ara-A were statistically significant (p = 0.03 and p = 0.01, respectively). In conclusion, STI571 used together with both the PNAs had an additive effect on CML CFU-GM cells. However, further experimental and clinical studies concerning the usefulness of these combinations in the treatment of CML patients seem warranted.
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PMID:The influence of imatinib mesylate (STI571) used alone or in combination with purine nucleoside analogues on the normal and chronic myelogenous leukaemia progenitor cells in vitro. 1456 59

To prevent the resistance to Glivec in patients with chronic myelogenous leukaemia (CML), it is necessary to get a good understanding of its potential mechanisms. The present hypothesis accents on the mechanisms whereby Bcr-Abl tyrosine kinase remains inhibited by Glivec, but alternative signalling pathways become activated-the potential reason associates with activation of telomerase after long-term treatment with Glivec and recovery of cell proliferation and immortality. The hypothesis is based on the observations about differences in telomere dynamics and telomerase activity between chronic and blast phases of CML patients, as well as about the potential effect of Glivec on the cross-talk between telomerase, Bcr-Abl tyrosine kinase and protein kinase C family-key enzymes in CML. It proceeds from recently published data, demonstrating that protein kinase C activates and c-Abl tyrosine kinase inhibits telomerase. During optimization of chemical structure, Glivec loose its effect on protein kinase C and enhances the effect on Bcr-Abl tyrosine kinase, resulting in a high potential to activate telomerase indirectly through its effect on both kinases. Experimental preclinical data are given in confirmation of this hypothesis.
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PMID:Cross-talk between Bcr-Abl tyrosine kinase, protein kinase C and telomerase-a potential reason for resistance to Glivec in chronic myelogenous leukaemia. 1459 45


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